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    Summary
    EudraCT Number:2012-003457-28
    Sponsor's Protocol Code Number:CC-486-AML-001
    National Competent Authority:Portugal - INFARMED
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2012-12-05
    Trial results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedPortugal - INFARMED
    A.2EudraCT number2012-003457-28
    A.3Full title of the trial
    A phase 3, Randomized, Double-Blind, Placebo-Controlled Study to Compare Efficacy and Safety of Oral Azacitidine plus Best Supportive Care Versus Best Supportive Care as Maintenance Therapy in Subjects with Acute Myeloid Leukemia in Complete Remission
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    The Efficacy and Safety of Oral Azacitidine Plus Best Supportive Care
    Versus Placebo and Best Supportive Care in Subjects with Acute Myeloid Leukemia (AML) no longer experiences symptoms of the disease
    A.3.2Name or abbreviated title of the trial where available
    QUAZAR AML maintenance
    A.4.1Sponsor's protocol code numberCC-486-AML-001
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorCelgene Corporation
    B.1.3.4CountryUnited States
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportCelgene Corporatiron
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationCelgene Corporation
    B.5.2Functional name of contact pointClinicalTrialDisclosure
    B.5.3 Address:
    B.5.3.1Street Address9225 Indian Creek Parkway, Suite 900
    B.5.3.2Town/ cityKansas
    B.5.3.3Post code66210
    B.5.3.4CountryUnited States
    B.5.4Telephone number+18882601599
    B.5.5Fax number+19132660394
    B.5.6E-mailClinicalTrialDisclosure@celgene.com
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community Yes
    D.2.5.1Orphan drug designation numberEU/3/07/509
    D.3 Description of the IMP
    D.3.1Product nameOral Azacitidine
    D.3.2Product code CC-486
    D.3.4Pharmaceutical form Film-coated tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNAZACITIDINE
    D.3.9.1CAS number 320-67-2
    D.3.9.4EV Substance CodeSUB05624MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number150
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 2
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community Yes
    D.2.5.1Orphan drug designation numberEU/3/07/509
    D.3 Description of the IMP
    D.3.1Product nameOral Azacitidine
    D.3.2Product code CC-486
    D.3.4Pharmaceutical form Film-coated tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNAZACITIDINE
    D.3.9.1CAS number 320-67-2
    D.3.9.4EV Substance CodeSUB05624MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number200
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboFilm-coated tablet
    D.8.4Route of administration of the placeboOral use
    D.8 Placebo: 2
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboFilm-coated tablet
    D.8.4Route of administration of the placeboOral use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Acute Myeloid leukemia in complete remission
    E.1.1.1Medical condition in easily understood language
    Acute Myeloid Leukemia (AML) no longer experiences symptoms of the disease
    E.1.1.2Therapeutic area Diseases [C] - Blood and lymphatic diseases [C15]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.0
    E.1.2Level PT
    E.1.2Classification code 10000881
    E.1.2Term Acute myeloid leukaemia (in remission)
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    The primary objective of the study is to evaluate whether maintenance therapy with oral azacitidine improves OS compared with placebo in subjects with AML, age ≥55 years, who have achieved first CR or CRi after induction with intensive chemotherapy with or without consolidation chemotherapy
    E.2.2Secondary objectives of the trial
    - To determine relapse-free survival ;
    - To determine safety, tolerability; and
    - To determine the effect of oral azacitidine compared with placebo on HRQoL and healthcare resource utilization.

    Exploratory objectives:

    - To determine plasma concentration of azacitidine and explore
    exposure-response relationships of efficacy and safety endpoints;
    - To determine complete cytogenetic remission rate;
    - To evaluate molecular and/or cellular markers in the bone marrow post-induction and during maintenance therapy that may be predictive of clinical outcomes with therapy (placebo or oral azacitidine), including OS and RFS, following CR/CRi; and
    - To evaluate exploratory HRQoL measures.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Male or female subjects ≥55 years of age at the time of signing the ICD;
    2. Newly diagnosed, histologically confirmed de novo AML or AML secondary to prior myelodysplastic disease or CMML;
    3. Should have undergone induction therapy with intensive chemotherapy with or without consolidation therapy;
    4. Must have achieved first CR/CRi status within 4 months(+/-7days) prior to randomization;
    5. ECOG performance status of 0, 1, 2 or 3;
    6. Adequate bone marrow function based on ANCs ≥ 0.5 x 109/L and platelet counts ≥ 20 x 109/L
    7. Adequate organ function, defined as:
    • Serum bilirubin ≤1.5 times the upper limit of normal;
    • Serum aspartate aminotransferase and alanine aminotransferase ≤2.5 times the ULN;
    • Serum creatinine ≤ 2.5 times the ULN;
    8. FCBP may participate, providing they meet the following conditions:
    • Agree to practice abstinence; or
    • Agree to use at least two effective contraceptive methods (oral, injectable, or implantable hormonal contraceptive; tubal ligation; intra-uterine device; barrier contraceptive with spermicide; or vasectomized partner) throughout the study, and for 3 months following the last dose of oral azacitidine; and
    • Have a negative serum pregnancy test (sensitivity of at least 25 mIU/mL) at screening; and
    • Have a negative serum or urine pregnancy test (Investigator’s discretion) within 72 hours prior to starting study therapy in the double-blind treatment phase (note that the screening serum pregnancy test can be used as the test prior to starting study therapy in the double-blind treatment phase if it is performed within the 72 hour timeframe).
    9. Male subjects with a female partner of childbearing potential must agree to practice abstinence or to the use of a physician-approved contraceptive method throughout the course of the study and avoid fathering a child during the course of the study and for 3 months following the last dose of azacitidine.

    At the Investigator's discretion and with approval of the sponsor, subjects meeting all of the following eligibility criteria are elegible to enter the extension phase (EP):
    1. All subjects randomized into the oral azacitidine or placebo arm and are continuing in either the Treatment Phase or
    Follow-up Phase of the CC-486-AML-001 study;
    - Subjects randomized to oral azacitidine treatment arm and continuing in the Treatment Phase demonstrating clinical benefit as assessed by the Investigator are elegible to receive oral azacitidine in the EP;
    - Subjects randomized into placebo arm of the study will not receive oral azacitidine in the EP, but will be followed for survival in the EP;
    - Subjects currently in the Follow-up Phase will continue to be followed for survival in the EP;
    2. Subjects who have signed the Informed Consent for the EP of the study;
    3. Subjects who do not meet any of the criteria for study discontinuation (see Section 12 of the Protocol).
    E.4Principal exclusion criteria
    1. Suspected or proven acute promyelocytic leukemia (FAB M3) based on morphology, immunophenotype, molecular assay, or karyotype; or AML with previous hematologic disorder such as chronic myeloid leukemia or myeloproliferative neoplasms, excluding MDS and CMML;
    2. AML associated with inv(16), t(8;21), t(16;16), t(15;17), or t(9;22) karyotypes or molecular evidence of such translocations;
    3. Prior bone marrow or stem cell transplantation;
    4. Have achieved CR/CRi following therapy with hypomethylating agents;
    5. Received therapy with hypomethylating agents for MDS and went on to develop AML within four months of discontinuing the therapy with hypomethylating agents;
    6. Proven central nervous system leukemia;
    7. Candidate for allogeneic bone marrow or stem cell transplant at screening;
    8. Diagnosis of malignant disease within the previous 12 months (excluding basal cell carcinoma of the skin without complications, “in-situ” carcinoma of the cervix or breast, or other local malignancy excised or irradiated with a high probability of cure);
    9. Unstable angina, significant cardiac arrhythmia, or New York Heart Association class 3 or 4 congestive heart failure
    10. Uncontrolled systemic fungal, bacterial, or viral infection (defined as ongoing signs/symptoms related to the infection without improvement despite appropriate antibiotics or other treatment);
    11. Known active viral infection with known human immunodeficiency virus or viral hepatitis type B or C ;
    12. Known or suspected hypersensitivity to azacitidine or mannitol;
    13. Use of any other experimental drug or therapy within 28 days prior to Day 1 of Cycle 1.
    E.5 End points
    E.5.1Primary end point(s)
    Overall Survival
    E.5.1.1Timepoint(s) of evaluation of this end point
    Estimated at 60 months after study initiation (approx. 330 deaths in total)
    E.5.2Secondary end point(s)
    - RFS;
    -Time to relapse from CR/CRi;
    -Time to discontinuation from treatment;
    -Safety / tolerability (type, frequency, severity, and relationship of AEs to study treatments; physical examinations, vital signs; clinical laboratory evaluations, and concomitant medication/therapy);
    - Patient-reported outcomes utilizing the FACIT-Fatigue Scale and the EQ-5D; and
    - Measures of healthcare resource utilization
    E.5.2.1Timepoint(s) of evaluation of this end point
    Estimated at 60 months after study initiation (approx. 330 deaths in total)
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic Yes
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group Yes
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial2
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned4
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA76
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Australia
    Austria
    Belgium
    Brazil
    Canada
    Czech Republic
    Finland
    France
    Germany
    Ireland
    Israel
    Italy
    Korea, Republic of
    Lithuania
    Mexico
    Poland
    Portugal
    Russian Federation
    Spain
    Taiwan
    Turkey
    United Kingdom
    United States
    E.8.7Trial has a data monitoring committee Yes
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    The study will conclude once the total number of events (n=330 deaths) have occurred.
    The End of Trial is defined as either the date of the last visit of the last subject to complete the post-treatment follow-up, or the date of receipt of the last data point from the last subject that is required for primary and/or secondary analysis, as pre-specified in the protocol, whichever is the later date
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years7
    E.8.9.1In the Member State concerned months7
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years7
    E.8.9.2In all countries concerned by the trial months7
    E.8.9.2In all countries concerned by the trial days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 115
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 345
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state27
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 300
    F.4.2.2In the whole clinical trial 460
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    The Extension Phase of the stydy will close once oral azacitidine becomes commercially available and reimbursed in the participating countries for the indication that the subject is being treated such that the subject's access to oral azacitidine is neither interrupted nor discontinued
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2013-01-10
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2013-02-01
    P. End of Trial
    P.End of Trial StatusCompleted
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